Accurate staging of high-risk localised, advanced, and metastatic prostate cancer is becoming increasingly more important in guiding local and systemic treatment. Gallium-68 prostate-specific ...membrane antigen (PSMA) positron emission tomography (PET) has increasingly been utilised globally to assess the local and metastatic burden of prostate cancer, typically in biochemically recurrent or advanced disease. Following our previous meta-analysis, a high-volume series has been reported highlighting the utility of 68Ga-PSMA PET in this setting.
To perform a systematic review and meta-analysis to update reported predictors of positive 68Ga-PSMA PET according to prior therapy and proportion of positivity in various anatomical locations with sensitivity and specificity profiles.
We performed critical reviews of MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science databases in July 2018 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality assessment was performed using Quality Assessment if Diagnostic Accuracy Studies-2 tool. Meta-analyses of proportions were performed using a random-effect model. Summary sensitivity and specificity values were obtained by fitting bivariate hierarchical regression models.
A total of 37 articles including 4790 patients were analysed. For patients with biochemical recurrence, positive 68Ga-PSMA PET scans increased with higher pre-PET prostate-specific antigen (PSA) levels. For PSA categories 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99, and ≥2ng/ml, the percentages of positive scans were 33%, 45%, 59%, 75%, and 95%, respectively. No significant differences in positivity were noted between Gleason sums ≤7 and ≥8. Significant differences in positivity after biochemical recurrence in the prostate bed were noted between radical prostatectomy (22%) and radiotherapy (52%) patients. On per-node analysis, high sensitivity (75%) and specificity (99%) were observed.
Ga-68-PSMA PET improves detection of metastases with biochemical recurrence, particularly at low pre-PET PSA levels of >0.2ng/ml (33%) and 0.2–0.5ng/ml (45%). Ga-68-PSMA-PET produces favourable sensitivity and specificity profiles on meta-analysis of pooled data. This analysis highlights different anatomic patterns of metastatic spread according to PSMA PET in the primary and biochemically recurrent settings.
Gallium-68 prostate-specific membrane antigen positron emission tomography is now an established imaging technique that has been developed in response to inadequacies in standard of care imaging modalities to improve the detection of metastatic disease in prostate cancer, particularly in the setting of disease recurrence. To date, this imaging modality in the setting of primary staging is controversial, given the paucity of data. In light of the growing body of evidence, we summarised the data to date to provide clinicians with an overview of this imaging modality.
Gallium-68 prostate-specific membrane antigen positron emission tomography is now an established imaging technique that has been developed in response to inadequacies in standard-of-care imaging modalities to improve the detection of metastatic disease in prostate cancer. In light of the growing body of evidence, we summarised the data to date to provide clinicians with an overview of this imaging modality.
Lung cancer affects over 1. 8 million people worldwide and is the leading cause of cancer related mortality globally. Currently, diagnosis of lung cancer involves a combination of imaging and ...invasive biopsies to confirm histopathology. Non-invasive diagnostic techniques under investigation include "liquid biopsies" through a simple blood draw to develop predictive and prognostic biomarkers. A better understanding of circulating tumor cell (CTC) dissemination mechanisms offers promising potential for the development of techniques to assist in the diagnosis of lung cancer. Enumeration and characterization of CTCs has the potential to act as a prognostic biomarker and to identify novel drug targets for a precision medicine approach to lung cancer care. This review will focus on the current status of CTCs and their potential diagnostic and prognostic utility in this setting.
Metastatic renal cell carcinoma (mRCC) is a disease that portends poor prognosis despite an increasing number of novel systemic treatment options including new targeted therapies and immunotherapy. ...Ablative intervention directed at oligometastatic RCC has demonstrated survival benefit. Consequently, developing techniques for improved staging of mRCC on contemporary imaging modalities including X-ray computed tomography (CT), magnetic resonance imaging (MRI) and/or bone scan (BS) is a clinical priority. This is relevant for metastatic deposits too small to characterize or lymph nodes within physiological normality. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly expressed on prostate cancer epithelial cells. Recently, small molecules targeting the PSMA receptor, linked to radioactive isotopes have been developed for use with positron emission tomography (PET). Despite its nomenclature, PSMA has also been found to be expressed in the neovasculature of non-prostate cancers such as renal cell carcinoma (RCC) and hence PSMA PET/CT imaging has been proposed as an alternative staging modality. Preliminary small studies involving the use of PSMA PET/CT imaging in mRCC have been encouraging with evidence of improved staging sensitivity which has directly led to change in management in some cases. Given these early encouraging reports, we performed a comprehensive narrative review on the available evidence, including the scientific basis for PSMA expression in RCC, the role of PSMA PET/CT imaging with potential clinical implications in mRCC, its limitations and future opportunities.
Recent technical advances have enabled for the first time, reliable in vitro culture of prostate cancer samples as prostate cancer organoids. This breakthrough provides the significant possibility of ...high throughput drug screening covering the spectrum of prostate cancer phenotypes seen clinically. These advances will enable precision medicine to become a reality, allowing patient samples to be screened for effective therapeutics ex vivo, with tailoring of treatments specific to that individual. This will hopefully lead to enhanced clinical outcomes, avoid morbidity due to ineffective therapies and improve the quality of life in men with advanced prostate cancer.
Despite efforts to improve earlier diagnosis of non-small cell lung cancer (NSCLC), most patients present with advanced stage disease, which is often associated with poor survival outcomes with only ...15% surviving for 5 years from their diagnosis. Tumour tissue biopsy is the current mainstream for cancer diagnosis and prognosis in many parts of the world. However, due to tumour heterogeneity and accessibility issues, liquid biopsy is emerging as a game changer for both cancer diagnosis and prognosis. Liquid biopsy is the analysis of tumour-derived biomarkers in body fluids, which has remarkable advantages over the use of traditional tumour biopsy. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) are two main derivatives of liquid biopsy. CTC enumeration and molecular analysis enable monitoring of cancer progression, recurrence, and treatment response earlier than traditional biopsy through a minimally invasive liquid biopsy approach. CTC-derived
cultures are essential to understanding CTC biology and their role in metastasis, provide a means for personalized drug testing, and guide treatment selection. Just like CTCs, ctDNA provides opportunity for screening, monitoring, treatment evaluation, and disease surveillance. We present an updated review highlighting the prognostic and therapeutic significance of CTCs and ctDNA in NSCLC.
Prostate cancer is the most commonly diagnosed solid-organ cancer amongst males worldwide. Metastatic castrate-resistant prostate cancer (mCRPC) is a rapidly fatal end-sequelae of prostate cancer. ...Therapeutic options for men with mCRPC are limited and are not curative in nature. The recent development of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of treatment-resistant haematological malignancies, and several studies are underway investigating the utility of this technology in the treatment of solid tumours. In this review, we evaluate the current treatment options for men with mCRPC as well as the current landscape of preclinical and clinical trials of CAR-T cell therapy against prostate cancer. We also appraise the various prostate cancer-specific tumour-associated antigens that may be targeted by CAR-T cell technology. Finally, we examine the potential translational barriers of CAR-T cell therapy in solid tumours. Despite preclinical success, preliminary clinical trials in men with prostate cancer have had limited efficacy. Therefore, further clinically translatable preclinical models are required to enhance the understanding of the role of this investigational therapeutic in men with mCRPC. In the era of precision medicine, tailored immunotherapy administered to men in a tumour-agnostic approach provides hope to a group of men who otherwise have few treatment options available.
Prostate cancer (PCa) patient-derived xenografts (PDXs) are commonly propagated by serial transplantation of "pieces" of tumour in mice, but the cellular composition of pieces is not standardised. ...Herein, we optimised a microwell platform, the Microwell-mesh, to aggregate precise numbers of cells into arrays of microtissues, and then implanted the Microwell-mesh into NOD-scid IL2γ
(NSG) mice to study microtissue growth. First, mesh pore size was optimised using microtissues assembled from bone marrow-derived stromal cells, with mesh opening dimensions of 100×100 μm achieving superior microtissue vascularisation relative to mesh with 36×36 μm mesh openings. The optimised Microwell-mesh was used to assemble and implant PCa cell microtissue arrays (hereafter microtissues formed from cancer cells are referred to as microtumours) into mice. PCa cells were enriched from three different PDX lines, LuCaP35, LuCaP141, and BM18. 3D microtumours showed greater in vitro viability than 2D cultures, but neither proliferated. Microtumours were successfully established in mice 81% (57 of 70), 67% (4 of 6), 76% (19 of 25) for LuCaP35, LuCaP141, and BM18 PCa cells, respectively. Microtumour growth was tracked using live animal imaging for size or bioluminescence signal. If augmented with further imaging advances and cell bar coding, this microtumour model could enable greater resolution of PCa PDX drug response, and lead to the more efficient use of animals. The concept of microtissue assembly in the Microwell-mesh, and implantation in vivo may also have utility in implantation of islets, hair follicles or other organ-specific cells that self-assemble into 3D structures, providing an important bridge between in vitro assembly of mini-organs and in vivo implantation.
Localised prostate cancer diagnosis and management is increasingly complex due to its heterogeneous progression and prognostic subgroups. Pitfalls in current screening and diagnosis have prompted the ...search for accurate and invasive molecular and genetic biomarkers for prostate cancer. Such tools may be able to distinguish clinically significant cancers from less aggressive variants to assist with prostate cancer risk stratification and guide decisions and healthcare algorithms. We aimed to provide a comprehensive review of the current prostate cancer biomarkers available and in development.
MEDLINE and EMBASE databases searches were conducted to identify articles pertaining to the use of novel biomarkers for prostate cancer.
A growing number of novel biomarkers are currently under investigation. Such markers include urinary biomarkers, serology-based markers or pathological tissue assessments of molecular and genetic markers. While limited clinical data is present for analysis, early results appear promising. Specifically, a combination of serum and urinary biomarkers (Serum PSA + Urinary PCA3 + Urinary TMPRSS2-ERG fusion) appears to provide superior sensitivity and specificity profiles compared to traditional diagnostic approaches (AUC 0.88).
The accurate diagnosis and risk stratification of prostate cancer is critical to ensure appropriate intervention. The development of non-invasive biomarkers can add to the information provided by current screening practices and allows for individualised risk stratification of patients. The use of these biomarkers appears to increase the sensitivity and specificity of diagnosis of prostate cancer. Further studies are necessary to define the appropriate use and time points of each biomarker and their effect on the management algorithm of prostate cancer.
Precision medicine approaches that inform clinical management of individuals with cancer are progressively advancing. Patient-derived explants (PDEs) provide a patient-proximal
platform that can be ...used to assess sensitivity to standard of care (SOC) therapies and novel agents. PDEs have several advantages as a patient-proximal model compared to current preclinical models, as they maintain the phenotype and microenvironment of the individual tumor. However, the longevity of PDEs is not compatible with the timeframe required to incorporate candidate therapeutic options identified by whole exome sequencing (WES) of the patient's tumor. This review investigates how PDE longevity varies across tumor streams and how this is influenced by tissue preparation. Improving longevity of PDEs will enable individualized therapeutics testing, and thus contribute to improving outcomes for people with cancer.
Patient-derived xenograft (PDX) models have been established as important preclinical cancer models, overcoming some of the limitations associated with the use of cancer cell lines. The utility of ...prostate cancer PDX models has been limited by an inability to genetically manipulate them in vivo and difficulties sustaining PDX-derived cancer cells in culture. Viable, short-term propagation of PDX models would allow in vitro transfection with traceable reporters or manipulation of gene expression relevant to different studies within the prostate cancer field. Here, we report an organoid culture system that supports the growth of prostate cancer PDX cells in vitro and permits genetic manipulation, substantially increasing the scope to use PDXs to study the pathobiology of prostate cancer and define potential therapeutic targets. We have established a short-term PDX-derived in vitro cell culture system which enables genetic manipulation of prostate cancer PDXs LuCaP35 and BM18. Genetically manipulated cells could be re-established as viable xenografts when re-implanted subcutaneously in immunocompromised mice and were able to be serially passaged. Tumor growth of the androgen-dependent LuCaP35 PDX was significantly inhibited following depletion of the androgen receptor (AR) in vivo. Taken together, this system provides a method to generate novel preclinical models to assess the impact of controlled genetic perturbations and allows for targeting specific genes of interest in the complex biological setting of solid tumors.
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